Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury

FASEB J. 2015 May;29(5):1940-9. doi: 10.1096/fj.14-260299. Epub 2015 Jan 21.

Abstract

Exposure to hyperoxia results in acute lung injury. A pathogenic consequence of hyperoxia is endothelial injury. Macrophage migration inhibitory factor (MIF) has a cytoprotective effect on lung endothelial cells; however, the mechanism is uncertain. We postulate that the MIF receptor CD74 mediates this protective effect. Using adult wild-type (WT), MIF-deficient (Mif(-/-)), CD74-deficient (Cd74(-/-)) mice and MIF receptor inhibitor treated mice, we report that MIF deficiency or inhibition of MIF receptor binding results in increased sensitivity to hyperoxia. Mif(-/-) and Cd74(-/-) mice demonstrated decreased median survival following hyperoxia compared to WT mice. Mif(-/-) mice demonstrated an increase in bronchoalveolar protein (48%) and lactate dehydrogenase (LDH) (68%) following 72 hours of hyperoxia. Similarly, treatment with MIF receptor antagonist resulted in a 59% and 91% increase in bronchoalveolar lavage protein and LDH, respectively. Inhibition of CD74 in primary murine lung endothelial cells (MLECs) abrogated the protective effect of MIF, including decreased hyperoxia-mediated AKT phosphorylation and a 20% reduction in the antiapoptotic effect of exogenous MIF. Treatment with MIF decreased hyperoxia-mediated H2AX phosphorylation in a CD74-dependent manner. These data suggest that therapeutic manipulation of the MIF-CD74 axis in lung endothelial cells may be a novel approach to protect against acute oxidative stress.

Keywords: H2AX; MIF; apoptosis; endothelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / etiology
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / prevention & control*
  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Female
  • Fluorescent Antibody Technique
  • Hyperoxia / complications*
  • Hyperoxia / physiopathology
  • Intramolecular Oxidoreductases / physiology*
  • Macrophage Migration-Inhibitory Factors / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Immunologic / physiology*

Substances

  • Macrophage Migration-Inhibitory Factors
  • Receptors, Immunologic
  • macrophage migration inhibitory factor receptor
  • Intramolecular Oxidoreductases
  • Mif protein, mouse